EP3049378A1 - Preparation of radioiodinated 3-fluoropropyl-nor-beta-cit - Google Patents
Preparation of radioiodinated 3-fluoropropyl-nor-beta-citInfo
- Publication number
- EP3049378A1 EP3049378A1 EP14849233.3A EP14849233A EP3049378A1 EP 3049378 A1 EP3049378 A1 EP 3049378A1 EP 14849233 A EP14849233 A EP 14849233A EP 3049378 A1 EP3049378 A1 EP 3049378A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- reaction mixture
- reaction
- fluoropropyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 50
- XQNMZKNFKRXLAD-UHFFFAOYSA-N 3-fluoropropanal Chemical compound FCCC=O XQNMZKNFKRXLAD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 71
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 239000011541 reaction mixture Substances 0.000 claims description 44
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 23
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- VNHWPVLQRKKKRY-UHFFFAOYSA-N 1-bromo-3-fluoropropane Chemical compound FCCCBr VNHWPVLQRKKKRY-UHFFFAOYSA-N 0.000 claims description 7
- 238000010520 demethylation reaction Methods 0.000 claims description 7
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 5
- 229940100198 alkylating agent Drugs 0.000 claims description 5
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 claims description 5
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 claims description 5
- 230000017858 demethylation Effects 0.000 claims description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 4
- 229960001479 tosylchloramide sodium Drugs 0.000 claims description 4
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 3
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 claims description 3
- URBUZQPPQLQHBZ-UHFFFAOYSA-N 1-fluoro-3-iodopropane Chemical compound FCCCI URBUZQPPQLQHBZ-UHFFFAOYSA-N 0.000 claims description 2
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 238000010791 quenching Methods 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- MPSNEAHFGOEKBI-UHFFFAOYSA-N anhydroecogonine methyl ester Natural products COC(=O)C1=CCC2CCC1N2C MPSNEAHFGOEKBI-UHFFFAOYSA-N 0.000 abstract description 6
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 abstract description 6
- MPSNEAHFGOEKBI-VXNVDRBHSA-N Anhydroecgonine methyl ester Chemical compound COC(=O)C1=CC[C@@H]2CC[C@H]1N2C MPSNEAHFGOEKBI-VXNVDRBHSA-N 0.000 abstract description 5
- DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical compound C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 abstract description 4
- 230000029936 alkylation Effects 0.000 abstract description 4
- 238000005804 alkylation reaction Methods 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 239000007818 Grignard reagent Substances 0.000 description 11
- 150000004795 grignard reagents Chemical class 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 230000000779 depleting effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000935 solvent evaporation Methods 0.000 description 3
- KXFSUVJPEQYUGN-UHFFFAOYSA-N trimethyl(phenyl)silane Chemical class C[Si](C)(C)C1=CC=CC=C1 KXFSUVJPEQYUGN-UHFFFAOYSA-N 0.000 description 3
- UKTSSJJZFVGTCG-UHFFFAOYSA-N (4-bromophenyl)-trimethylsilane Chemical compound C[Si](C)(C)C1=CC=C(Br)C=C1 UKTSSJJZFVGTCG-UHFFFAOYSA-N 0.000 description 2
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000012217 radiopharmaceutical Substances 0.000 description 2
- 229940121896 radiopharmaceutical Drugs 0.000 description 2
- 230000002799 radiopharmaceutical effect Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229950009390 symclosene Drugs 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- NLRJUIXKEMCEOH-UHFFFAOYSA-N 3-fluoropropan-1-ol Chemical compound OCCCF NLRJUIXKEMCEOH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical group C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K51/0448—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil tropane or nortropane groups, e.g. cocaine
Definitions
- the present invention relates to improved processes for the preparation of radioiodinated 3-fluoropropyl-nor-3-CIT.
- radioiodinated 3-fluoropropyl-nor-3-CIT (i.e., compound I) is a diagnostic agent useful for diagnosing and monitoring movement disorders and dementia, and has specific use in the diagnosis and monitoring of Parkinson's disease.
- 1-123 radioiodinated 3-fluoropropyl-nor-3-CIT has the following structure:
- This compound can be prepared from anhydroecgonine methyl ester using a six step process, which relies on the conversion of an arylstannane precursor to the 1-123 labeled compound.
- a six step process is generally disclosed in, for example, Swahn, et al., Journal of Labelled Compounds and Radiopharmaceuticals, 1996, Vol.
- the present invention is directed to a process for preparation of compound (I) comprising the following reaction scheme:
- the present invention is directed to a process for the preparation of a N-(3-fluoropropyl) compound (III), the process comprising contacting a nortropane compound (II) with 3-fluoropropanal to form compound (III):
- R 1 is selected from the group consisting of halogen, ⁇ - ⁇ Si(CH 3 ) 3 , and ⁇ - ⁇ Sn(CH 3 ) 3 .
- the present invention relates to the preparation of 1-123 radioiodinated 3-fluoropropyl-nor-3-CIT using an arylsilane intermediate.
- the process avoids the use of hexamethylditin, and has a reduced number of steps as compared to previously known processes for the preparation of radioiodinated 3- fluoropropyl-nor-3-CIT from anhydroecgonine methyl ester (compound 1-1).
- the present invention also relates to the alkylation of a nortropane to the corresponding N-(3-fluoropropyl) analogue using 3-fluoropropanal. The process avoids the use of the ozone depleting compound 3-fluoro-l-bromopropane.
- the present invention provides a process for the preparation of compound (I) comprising the following reaction scheme:
- the present invention is directed to a process for the preparation of a N-(3-fluoropropyl) compound (III), the process comprising contacting a nortropane compound (II) with 3-fluoropropanal to form compound (III):
- R 1 is selected from the group consisting of halogen, ⁇ - ⁇ Si(CH 3 ) 3 , and ⁇ - ⁇ Sn(CH 3 ) 3 .
- the present invention relates to the preparation of I- 123 radioiodinated 3-fluoropropyl-nor-3-CIT (compound I) using an arylsilane intermediate.
- the process avoids the use of hexamethylditin, and reduces the number of steps previously required for the preparation of radioiodinated 3-fluoropropyl-nor-3-CIT from anhydroecgonine methyl ester (compound 1-1).
- Step A of the process involves or comprises the formation of an arylsilane precursor by reacting anhydroecogonine methyl ester (compound 1-1) with a halogen-substituted phenyltrimethylsilane in a Grignard addition reaction:
- X is a halogen, and preferably is I or Br.
- a Grignard reagent may be prepared by contacting the halogen- substituted phenyltrimethylsilane with magnesium in the presence of a solvent.
- Suitable solvents for use in formation of the Grignard reagent include ethereal solvents, such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, diethyl ether, and the like.
- the halogen-substituted phenyltrimethylsilane is typically present in the solvent in at a molar concentration of from about 0.2 M to about 1.0 M.
- the reaction mixture may optionally further include or comprise a compound for initiating formation of the Grignard reagent.
- Suitable compounds include an iodine crystal or ethylene dibromide.
- the compound is preferably included in the reaction mixture in an amount sufficient to catalyze formation of the Grignard reagent.
- the reaction may be conducted at a variety of temperatures, for example, from about 30°C to about 90°C, and preferably is conducted at reflux.
- the reaction is allowed to proceed until substantially complete, and typically for at least 30 minutes, and more typically from about 30 minutes to about 180 minutes, or from about 45 minutes to about 180 minutes.
- the Grignard reagent forming reaction may be conducted under an inert atmosphere, such as argon or nitrogen.
- the solution comprising the Grignard reagent is contacted with compound 1-1 to form an arylsilane precursor (compound 2-1).
- the Grignard reagent is preferably present in the reaction mixture in an amount of from about 2.2 to about 2.4 equivalents relative to compound 1-1 (e.g., about a 2.2:1 to about a 2.4:1 molar equivalent).
- an additional solvent may be added to the reaction mixture.
- suitable solvents include methylene chloride, tetrahydrofuran, diethyl ether, 2-methyltrethydrofuran, tert-butyl methyl ether, and the like.
- the solvent comprises methylene chloride and diethyl ether (e.g., diethyl ether added during preparation of the Grignard reagent) in a volume:volume ratio of about 1.2:1.
- compound 1-1 is present in the reaction mixture in a concentration of from about 0.1 M to about 0.3 M, and preferably is at a concentration of 0.17 M.
- the reaction may be conducted at a variety of temperatures, for example, from about -40°C to about -90°C, including from about -60°C to about - 85°C, and from about -75°C to about -80°C.
- the reaction is conducted at a temperature of -78°C and allowed to warm to 0°C. The reaction is allowed to proceed until completed, typically for at least 20 minutes.
- the temperature of the reaction mixture may be further lowered following reaction, for example, to a temperature of from about - 75°C to about -80°C, and preferably to a temperature of -78°C.
- the reaction is quenched with an acid, such as trifluoroacetic acid.
- the reaction mixture is allowed to warm following addition of compound 1-1, for example, to from about 0°C to about 22°C, and then cooled again to a temperature of from about -40°C to about -90°C, and preferably to a temperature of -78°C. Following this second cooling, the reaction may be quenched with an acid, such as trifluoroacetic acid to obtain the arylsilane precursor (compound 2-1). Typically, the acid is added to the reaction mixture in a 1:1 molar ratio with the Grignard reagent.
- an acid such as trifluoroacetic acid
- Compound 2-1 may be isolated from the reaction mixture using any suitable technique known in the art, including, for example, filtration, ether extraction, rotary evaporation of solvent, chromatography, or combinations thereof.
- Step B conversion of compound 2-1 to compound 3-1
- Step B of the process involves or comprises demethylating the arylsilane precursor (compound 2-1) to form compound 3-1:
- Suitable demethylation reagents include 1- chloroethylchloroformate, vinyl chloroformate, 2,2,2-triethylchloroformate, and the like.
- the demethylation reagent is preferably present in the reaction mixture in an amount of from about 1 equivalent to about 10 equivalents, and more preferably in an amount of about 7 equivalents, relative to compound 2-1.
- the reaction mixture may further include or comprise one or more aprotic solvent.
- suitable aprotic solvents include 1,2- dichloroethane, ethyl acetate, toluene, chloroform, and combinations thereof.
- the solvent is 1,2-dichloroethane or toluene.
- the solvent may be present in the reaction mixture in an amount of from about 1 mL to about 100 mL per gram of compound 2-1, and preferably in an amount of about 20 mL per gram of compound 2-1.
- the reaction mixture may optionally further include or comprise an inorganic base.
- suitable inorganic bases include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and combinations thereof.
- the reaction mixture typically comprises the inorganic base in a molar ratio of compound 2-1 to inorganic base of from about 1:1 to about 1:6.
- the demethylation reaction may result in formation of a carbamate intermediate compound.
- the mixture is typically concentrated and heated in methanol, to decompose the intermediate carbamate.
- the reaction mixture may optionally further comprise one or more reagents to assist in the decomposition of the intermediate carbamate. Suitable reagents include combinations of zinc and acetic acid.
- the demethylation reagent is 1- chloroethylchloroformate
- the reaction mixture contains about 7 equivalents of 1-chloroethylchloroformate relative to compound 2-1.
- the reaction mixture is heated to 80°C for 3 hours, followed by addition of N,N- diisopropylethylamine, and heating to 80°C for an additional 3 hours.
- Compound 3-1 may be isolated from the reaction mixture using any suitable technique known in the art, including, for example, filtration, chromatography, or combinations thereof.
- Step C conversion of compound 3-1 to compound 4-1
- Step C of the process involves or comprises the N-alkylation of compound 3-1 to form compound 4-1:
- compound 3-1 is contacted with a suitable alkylating agent, such as 3-fluoro-l-bromopropane, 3-fluoro-l-iodopropane, or 3- fluoropropanal.
- a suitable alkylating agent such as 3-fluoro-l-bromopropane, 3-fluoro-l-iodopropane, or 3- fluoropropanal.
- the alkylating agent is 3-fluoropropanal.
- 3-fluoropropanal is commercially available, or may be prepared by oxidation of 3- fluoropan-l-ol using Dess- Martin periodinane or trichloroisocyanuric acid and TEMPO (i.e., 2,2,6,6-tetramethyl-l-piperidinyloxy).
- the reaction mixture will comprise from about 1 to about 3 equivalents of alkylating agent, relative to compound 3-1.
- the reaction mixture may further comprise a solvent.
- suitable solvents include ethyl acetate, 1,2-dichloroethane, acetonitrile, dichloromethane, chloroform, and combinations thereof.
- the reaction mixture may include a reducing agent.
- suitable reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, and formic acid.
- the reducing agent is present in the reaction mixture in an amount of from about 2 equivalents to about 15 equivalents, relative to compound 3-1.
- Step D conversion of compound 4-1 to compound (I)
- Step D of the process is a radioiododesilation reaction, in which the trimethylsilane moiety of compound 4-1 is replaced with 1-123 to form compound (I):
- reaction mixture may further comprise a buffer, such as acetate.
- Non-limiting examples of suitable solvents include methanol, acetic acid, trifluoroacetic acid, and acetic acid in ethanol.
- Non-limiting examples of suitable oxidizing agents include Chloramine-T (i.e., (N-chloro-p-toluenesulfonamido)sodium), tert-butyl hypochlorite, peracetic acid, and combinations thereof.
- the reaction mixture may comprise a reagent, such as silver tetrafluoroborate, which increases the electrophilicity of the 1-123 source.
- the reaction mixture will comprise from about 0.6 to about 10 micrograms of compound 4-1 per mCi of 1-123 from the 1-123 source.
- the reaction mixture may comprise, per mCi of 1-123, from about 0.6 to about 10 micrograms of compound 4-1, about 3 microliters of trifluoroacetic acid, about 1.5 microliters of Chloramine-T, and about 0.25 microliters of methanokacetic acid (99:1).
- the reaction mixture comprises [ 123 l]Nal, chloramine-T, and trifluoroacetic acid.
- the reaction mixture comprises [ 123 I]ICI and silver tetrafluoroborate.
- the reaction mixture comprises [ 123 l]Nal and tert-butyl hypochlorite.
- the reaction mixture comprises [ 123 l]Nal and peracetic acid in acetate buffer.
- the reaction is typically conducted at a temperature of from about 21°C to about 25°C, and allowed to proceed for at least about 15 minutes, and typically from about 15 minutes to about 2 hours.
- reaction may be quenched by addition of a base, such as N H 4 OH, and compound (I) may be isolated using any suitable technique known in the art, such as solvent evaporation, chromatography, and combinations thereof.
- a base such as N H 4 OH
- suitable reaction conditions for Step D are described in, for example, Musachio, et al., Appl. Radiat. Isoi, 1996, Vol. 47, No. 1, p. 79-81.
- the present invention relates to the alkylation of a nortropane to the corresponding N-(3-fluoropropyl) analogue using 3- fluoropropanal.
- the process advantageously avoids the use of the ozone depleting compound 3-fluoro-l-bromopropane.
- R 1 is selected from the group consisting of halogen, ⁇ - ⁇ Si(CH 3 ) 3 , and ⁇ - ⁇ Sn(CH 3 ) 3 .
- the halogen is I.
- R 1 is I or ⁇ - ⁇ Si(CH 3 ) 3 .
- 3-fluoropropanal is commercially available, or may be prepared by oxidation of 3-fluoropan-l-ol using Dess-Martin periodinane or trichloroisocyanuric acid and TEMPO (i.e., 2,2,6,6-tetramethyl-l-piperidinyloxy) according to the following reaction:
- the reaction mixture may further comprise a solvent.
- suitable solvents include ethyl acetate, 1,2-dichoroethane, acetonitrile, dichloromethane, chloroform, and combinations thereof.
- R 1 is as defined above.
- a reducing agent in the reaction mixture to facilitate reduction of the iminium intermediate compound 1-2 to compound (III).
- suitable reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, and formic acid.
- the reducing agent is present in the reaction mixture in an amount of from about 2 equivalents to about 15 equivalents, relative to compound (II).
- the reducing agent may be added to the reaction mixture prior to or subsequent to reaction of compound (II) with the 3-fluoropropanal.
- the Grignard reagent was prepared as follows: The reaction was initiated by adding about 0.6 mL (4 mmol) of (4-bromophenyl)trimethylsilane to a suspension of magnesium (0.286 g, 12 mmol) and an iodine crystal in 7 mL of ether and heating at reflux in an oil bath. After the reaction initiated, the mixture was diluted with 7 mL of ether and the remaining 1.7 mL (8 mmol) of (4- bromophenyl)trimethylsilane was added. The mixture was then heated at reflux for 1.5 hr.
- reaction was worked up by concentrating in vacuo, adding 2 mL of 1:1 waterxoncentrated ammonium hydroxide. The mixture was extracted with three 1 mL portions of dichloromethane. The combined organic layers of each extraction were dried over sodium sulfate. A sample of the organic extracts was analyzed by gas chromatography, which showed 80% compound 3-1.
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PL14849233T PL3049378T3 (en) | 2013-09-25 | 2014-09-25 | Preparation of radioiodinated 3-fluoropropyl-nor-beta-cit |
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US201361882039P | 2013-09-25 | 2013-09-25 | |
PCT/US2014/057404 WO2015048250A1 (en) | 2013-09-25 | 2014-09-25 | Preparation of radioiodinated 3-fluoropropyl-nor-beta-cit |
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US (1) | US9339565B2 (en) |
EP (1) | EP3049378B1 (en) |
JP (2) | JP6224256B2 (en) |
AU (1) | AU2014326601B2 (en) |
BR (1) | BR112016006129A2 (en) |
CA (1) | CA2922723C (en) |
ES (1) | ES2711122T3 (en) |
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US9513907B2 (en) * | 2013-08-06 | 2016-12-06 | Intel Corporation | Methods, apparatus, instructions and logic to provide vector population count functionality |
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US4190601A (en) * | 1978-05-31 | 1980-02-26 | Union Carbide Corporation | Production of tertiary amines by reductive alkylation |
US6123917A (en) * | 1990-08-09 | 2000-09-26 | Research Triangle Institute | Method for making cocaine receptor binding ligands and intermediates therefor |
US5698179A (en) * | 1992-02-25 | 1997-12-16 | Neuro Imaging Technologies, Llc | Iodinated neuroprobe for mapping monoamine reuptake sites |
US6447747B1 (en) | 1996-10-29 | 2002-09-10 | Guilford Pharmaceuticals Inc. | Process for the preparation of radiopharmaceuticals |
FI104048B (en) * | 1997-06-16 | 1999-11-15 | Map Medical Technologies Oy | Process for the preparation of radioiodinated receptor substances for in vivo use |
CA2721484A1 (en) | 1999-05-12 | 2000-11-12 | President And Fellows Of Harvard College | Dopamine transporter imaging agents |
JP2001213881A (en) * | 2000-02-02 | 2001-08-07 | Nihon Medi Physics Co Ltd | Process for synthesis of anhydroecgonine derivative |
BRPI0414862A (en) * | 2003-10-03 | 2006-11-28 | Pfizer | imidazopyridine-substituted tropane derivatives with ccr5 receptor antagonist activity for the treatment of hiv and inflammation |
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EP2398808B1 (en) * | 2009-02-17 | 2013-11-20 | Mallinckrodt LLC | Process for the reductive alkylation of normorphinans |
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JP6423936B2 (en) | 2018-11-14 |
WO2015048250A1 (en) | 2015-04-02 |
BR112016006129A2 (en) | 2017-08-01 |
US20150087838A1 (en) | 2015-03-26 |
TR201901758T4 (en) | 2019-03-21 |
AU2014326601B2 (en) | 2018-01-18 |
CA2922723A1 (en) | 2015-04-02 |
AU2014326601A1 (en) | 2016-03-17 |
EP3049378A4 (en) | 2017-04-19 |
PL3049378T3 (en) | 2019-06-28 |
JP2016533390A (en) | 2016-10-27 |
US9339565B2 (en) | 2016-05-17 |
ES2711122T3 (en) | 2019-04-30 |
JP6224256B2 (en) | 2017-11-01 |
CA2922723C (en) | 2022-04-19 |
EP3049378B1 (en) | 2018-12-05 |
MX2016003035A (en) | 2016-06-10 |
JP2017218460A (en) | 2017-12-14 |
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